DGAP-News: Press Release: 4SC presents summary of biomarker and patient subgroup analysis of prognostic factors for survival in advanced HCC
(firmenpresse) - DGAP-News: 4SC AG / Key word(s): Miscellaneous
Press Release: 4SC presents summary of biomarker and patient subgroup
analysis of prognostic factors for survival in advanced HCC
30.09.2013 / 07:30
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Press Release
4SC presents summary of biomarker and patient subgroup analysis of
prognostic factors for survival in advanced HCC
- Baseline and biomarker characteristics of advanced HCC patients
identified that have an impact on overall survival (OS) and are
suitable as enrollment or stratification criteria in upcoming pivotal
HCC programme with resminostat
- Novel potentially predictive biomarker ZFP64 identified in both, in HCC
and in Hodgkin Lymphoma (HL) patients: high baseline expression of
ZFP64 observed in about 2/3 of patients correlates with doubling of
median OS under resminostat treatment compared to low ZFP64 expression
- Pharmacodynamic activity of resminostat on ZFP64 confirmed in patients
and cell lines: HDAC inhibition by resminostat treatment leads to
down-regulation of ZFP64, in peripheral blood of HCC patients
- Further information about proposed role of biomarker ZFP64 in HCC
tumour progression presented
- Poster presentation at ECCO 2013 conference, 30 Sept. 2013, Amsterdam
Planegg-Martinsried, Germany, 30 September 2013 - 4SC AG (Frankfurt, Prime
Standard: VSC), a discovery and development company of targeted small
molecule drugs for cancer and autoimmune diseases, today presents a
detailed summary of results of a patient subgroup analysis of prognostic
factors for overall survival and biomarkers in the Phase II SHELTER trial
in advanced liver cancer (HCC). The data will be presented in a poster
presentation today, 30 September 2013, from 2:00 PM - 4:30 PM (CEDT), at
the ECCO 2013 (European Cancer Congress 2013) in Amsterdam). The poster
will also be online at
www.4sc.de/product-pipeline/publications-posters/resminostat when the
session begins at 2:00 PM (CEDT).
As previously reported, the SHELTER trial investigated the HDAC inhibitor
resminostat both as a monotherapy and in combination with the cancer drug
sorafenib (Nexavar(R)) as a 2nd line treatment of advanced HCC patients
that had progressed under 1st line sorafenib therapy. In the study, the
combination of resminostat and sorafenib achieved a median overall survival
(OS) of 8.1 months. This constitutes an additional gain of almost 3 months
compared to the expected median OS of 5.2 months after progression on 1st
line sorafenib therapy (see data from the 1st line HCC SHORE trial with
sorafenib). 4SC is currently in preparation of pivotal clinical development
plans for resminostat in combination with sorafenib in advanced HCC.
Dr Bernd Hentsch, Chief Development Officer of 4SC AG; comments: 'The
identification of a number of most crucial patient characteristics relevant
for survival expectations will now be supportive to guide the setup for our
planned pivotal clinical development program with resminostat in advanced
HCC. Furthermore, in conjunction with the application of our potentially
predictive ZFP64 biomarker 4SC aims at developing resminostat into a
personalized cancer medicine for this indication.'
Summary of the results presented at ECCO 2013 in further detail:
1) Selected baseline characteristics correlate withoverall survival of
advanced HCC patients in the SHELTER study
4SC reports results from the analysis of HCC patient baseline
characteristics that appear to have an impact on overall survival in
advanced HCC patients of the SHELTER study, treated with either resminostat
monotherapy or in combination with sorafenib (Nexavar(R)). In the
monotherapy arm, an overall good performance status of the patients (ECOG
0) and pre-treatment with a local ablative therapy (transarterial
chemoembolization, TACE) correlated with a longer survival outcome. In the
combination therapy arm in addition to ECOG 0 also the absence of liver
cirrhosis (Child-Pugh A) and the absence of vascular invasion of the liver
tumour was identified to correlate with a prolonged overall survival.
Notably, in both treatment arms the time interval between end of 1st line
sorafenib therapy and 2nd line treatment start in the SHELTER study ('drug
holidays') had no influence on the median OS of SHELTER patients. These and
other factors will be considered as important enrollment and stratification
criteria for the currently planned pivotal Phase III studies with
resminostat in combination with sorafenib as a novel treatment option for
advanced HCC.
2) High baseline expression of ZFP64 correlates with prolonged survival in
cancer patients treated with resminostat; pharmacodynamic activity of
resminostat (i.e. down-regulation of ZFP64 gene expression) confirmed;
proposed role of ZFP64 in tumour progression further elaborated
In the search for suitable biomarkers that allow monitoring the
pharmacodynamic activity of resminostat 4SC identified a set of genes that
showed a robust and reproducible regulation of expression levels in
response to resminostat within hours after drug exposure in peripheral
blood of cancer patients. One of these highly regulated genes is the DNA
binding transcription factor 'zinc-finger protein 64' (ZFP64). According to
the current model of ZFP64 activity, this biomarker is expected to play a
role in HCC tumour progression by promoting processes of liver inflammation
and tumour progression in a dual way by (i) co-activation of NF-kB-mediated
pro-inflammatory TLR signaling, and (ii) by co-activating the
pro-tumourigenic Notch1 pathway. ZFP64 levels in peripheral blood samples
of HCC patients can be conveniently determined by quantitative PCR
technology. ZFP64 blood levels were rapidly reduced approx. 5-fold in
comparison to baseline levels within 2-5 hours after drug intake,
presumably reflecting a similar response at the patients' tumour site, also
suggested by similar results obtained in vitro in a variety of cancer cell
lines of different tumour origins.
Moreover, baseline expression of ZFP64 in HCC patients before the start of
treatment proved to correlate in a statistically significant manner
(p=0.04) with the achieved clinical outcome, i.e. higher baseline
expression was indicative of a longer overall survival than lower baseline
expression of ZFP64. High ZFP64 expression was observed in about 2/3 of the
patients, resulting in a doubling of the median OS value in comparison to
the 1/3 of patients with low baseline ZFP64 expression. Importantly, this
observation in advanced HCC patients of the SHELTER study treated with
either resminostat monotherapy or in combination with sorafenib
(Nexavar(R)) was confirmed in a second Phase II study (SAPHIRE) in advanced
Hodgkin Lymphoma (HL) patients treated with resminostat monotherapy,
indicating a potential predictive character of this biomarker for response
to resminostat treatment and suggesting a common underlying biological
background in certain tumours that might be more responsive to treatment
with resminostat.
Ends
Details of the Presentation
Abstract No.: 2.601
Poster Board P429
Abstract Title: Subgroup analysis of prognostic factors for overall
survival in the SHLTER trial evaluating resminostat in advanced
hepatocellular carcinoma (HCC)
Time/Place of Presentation: Monday, 30 September 2013, 2:00 PM - 4:30 PM
(CEDT)
Session: Gastrointestinal Malignancies - Noncolorectal
Authors: Michael Bitzer1, Anna Mais2, Bernhard Hauns2, Julia Asche2, Thomas
Herz2, Stefano Pegoraro2, Aldo Ammendola2, Stefan W. Henning2, Bernd
Hentsch2, and SHELTER Study Group
1 Medical University Clinic, Eberhard-Karls-University, Tuebingen, Germany;
2 4SC AG, Planegg-Martinsried, Germany
About Resminostat
Resminostat (4SC-201), 4SC's lead oncology compound, is an oral
histone-deacetylase (HDAC) inhibitor with an innovative epigenetic
mechanism of action that potentially enables the compound to be deployed as
a novel, targeted tumour therapy for a broad spectrum of oncological
indications, both in monotherapy and, in particular, in combination with
other cancer drugs. HDAC inhibitors have been shown to modify the DNA
structure of tumour cells to cause their differentiation and programmed
cell death (apoptosis) and are therefore considered to offer a mechanism of
action that has the particular potential to halt tumour progression and
induce tumour regression. Additionally, resminostat is also assumed to
induce what is known as tumour cell (re-)sensitisation to other anti-cancer
compounds. This process can suppress or reverse certain tolerance and
resistance mechanisms, which tumour cells often develop against other
cancer drugs. Supplementary treatment with resminostat can be expected to
restore or significantly improve the efficacy of a previously administered
cancer therapy which was no longer effective; furthermore, combining
resminostat and common cancer drugs right from the very beginning can also
be expected to effectively enhance the success of such a treatment.
Resminostat to date has been investigated in a broad clinical campaign
comprising liver cancer (hepatocellular carcinoma, HCC), Hodgkin's Lymphoma
(HL), and colorectal cancer (CRC), with non-small-cell lung cancer (NSCLC)
recently been added as a third solid cancer indication to the programme.
In the Phase II SAPHIRE trial in patients with advanced Hodgkin's Lymphoma
(HL), resminostat in monotherapy has demonstrated substantial anti-tumour
activity, with an overall response rate of 34% and a clinical benefit in
54% of the patients in a heavily pre-treated patient population together
with very good safety and tolerability. In the Phase II SHELTER study
resminostat has been evaluated as monotherapy and in combination with
sorafenib as a second-line treatment in advanced HCC after proven
radiological disease progression under first-line sorafenib therapy.
Patients receiving the resminostat/sorafenib combination therapy showed a
median overall survival of 8.1 months, a value to the company's best
knowledge not reached in any study with a comparable second-line patient
population. The resminostat/sorafenib combination therapy had shown a
progression-free survival rate (PFSR) after 12 weeks of 70.0% and a median
PFS of 5.4 months. The primary study endpoint was achieved ahead of
schedule in both the combination and the monotherapy group. Notably, in
both tumour indications, HCC and HL, gene expression levels of the new
biomarker ZFP64 measured prior to study treatment start in blood cells of
patients, were identified to be indicative of survival outcome upon
treatment with resminostat. Hereby, patients with a high level of ZFP64
gene expression at baseline experienced longer survival than patients with
low ZFP64 expression levels. Resminostat was further studied in a Phase I
dose escalation approach in advanced colorectal cancer (CRC) patients
evaluating resminostat in combination with the standard chemotherapeutic
FOLFIRI regimen. Positive results for safety and tolerability as well as
promising signs of clinical activity of this combination have been
published at the 2013 ASCO conference.
4SC is currently in discussions with regulatory agencies and potential
partners in order to prepare the next clinical steps to develop resminostat
in combination with sorafenib in a pivotal programme in first-line HCC
towards market approval.
About 4SC
The Group managed by 4SC AG (ISIN DE0005753818) discovers and develops
targeted, small-molecule drugs for treating diseases with high unmet
medical needs in cancer and autoimmune indications. These drugs are
intended to provide innovative treatment options that are more tolerable
and efficacious than existing therapies, and provide a better quality of
life. The Company's pipeline comprises promising products that are in
various stages of clinical development. 4SC's aim is to generate future
growth and enhance its enterprise value by entering into partnerships with
pharmaceutical and biotech companies. Founded in 1997, 4SC had 83 employees
at 30 March 2013. 4SC AG has been listed on the Prime Standard of the
Frankfurt Stock Exchange since December 2005.
Cautionary statement regarding forward-looking statements
This press release contains certain forward-looking statements. Any
forward-looking statement applies only on the date of this press release.
By their nature, forward-looking statements are subject to a number of
known and unknown risks and uncertainties that may or may not occur in the
future and as a result of which the actual results and performance may
differ substantially from the expected future results or performance
expressed or implied in the forward looking statements. No warranties or
representations are made as to the accuracy, achievement or reasonableness
of such statements, estimates or projections, and 4SC AG has no obligation
to update any such information or to correct any inaccuracies herein or
omission herefrom which may become apparent.
For more information please visit www.4sc.com or contact:
4SC AG
Jochen Orlowski, Corporate Communications&Investor Relations
jochen.orlowski(at)4sc.com, Tel.: +49-89-7007-6366
MC Services
Raimund Gabrie
raimund.gabriel(at)mc-services.eu , Tel.: +49-89-2102-2830
The Trout Group (USA)
Chad Rubin
Crubin(at)troutgroup.com, Tel.: +1-646-378-2947
End of Corporate News
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Language: English
Company: 4SC AG
Am Klopferspitz 19a
82152 Martinsried
Germany
Phone: +49 (0)89 7007 63-0
Fax: +49 (0)89 7007 63-29
E-mail: public(at)4sc.com
Internet: www.4sc.de
ISIN: DE0005753818
WKN: 575381
Listed: Regulierter Markt in Frankfurt (Prime Standard);
Freiverkehr in Berlin, Düsseldorf, München, Stuttgart
End of News DGAP News-Service
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